Mitochondrial Dysfunction and β-Cell Failure in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead to β-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochrome c release into cytosol and apoptosis. Group VIA phospholipase A2 (iPLA2β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA2β-deficiency increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM

Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2β). Here we show that genetic ablation of PLA2G6 in mice (iPLA2β-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2β-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease

doi:10.1155/2012/703538 Review Article Mitochondrial Dysfunction and β-Cell Failure in Type 2 Diabetes Mellitus

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead to β-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochrome c release into cytosol and apoptosis. Group VIA phospholipase A2 (iPLA2β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA2β-deficiency increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM. 1

A tripeptide Diapin effectively lowers blood glucose levels in male type 2 diabetes mice by increasing blood levels of insulin and GLP-1.

The prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide. Effective therapies, such as insulin and Glucagon-like peptide-1 (GLP-1), require injections, which are costly and result in less patient compliance. Here, we report the identification of a tripeptide with significant potential to treat T2D. The peptide, referred to as Diapin, is comprised of three natural L-amino acids, GlyGlyLeu. Glucose tolerance tests showed that oral administration of Diapin effectively lowered blood glucose after oral glucose loading in both normal C57BL/6J mice and T2D mouse models, including KKay, db/db, ob/ob mice, and high fat diet-induced obesity/T2D mice. In addition, Diapin treatment significantly reduced casual blood glucose in KKay diabetic mice in a time-dependent manner without causing hypoglycemia. Furthermore, we found that plasma GLP-1 and insulin levels in diabetic models were significantly increased with Diapin treatment compared to that in the controls. In summary, our findings establish that a peptide with minimum of three amino acids can improve glucose homeostasis and Diapin shows promise as a novel pharmaceutical agent to treat patients with T2D through its dual effects on GLP-1 and insulin secretion

Time dependent effect of Diapin on blood glucose level in <i>KKay</i> diabetic mice.

<p>Male <i>KKay</i> diabetic mice were randomly divided into control and treated groups. In control group (•), the mice were fed with regular chaw diet. The mice in the treated groups were fed with regular chow diet containing 6 (Δ) and 12 g/kg Diapin (▪), respectively. The casual blood glucose levels were monitored weekly. n = 10, *<i>p</i><0.05, compared with the control.</p

Effect of Diapin on blood glucose in C57BL/6J mice during IPGTT.

<p>The mice were orally given vehicle in the control group (n = 10) and Diapin (1 mg/g, n = 10) in the treated group and followed by IPGTT. *<i>P</i><0.05, compared with the controls.</p

Effect of Diapin on plasma insulin levels in <i>KKay</i> diabetic mice.

<p><b>A.</b> Insulin levels in mouse plasma. The fasted male <i>KKay</i> mice were randomly divided into two groups (n = 11/group) and orally given glucose or glucose plus Diapin, respectively. Blood samples were collected 30 min after administration of glucose and plasma insulin levels were measured. <b>B.</b> Diapin concentration in mouse plasma. The fasted male C57BL/6J mice were orally loaded with Diapin at 1 mg/g bw plus glucose 2 mg/g. Blood samples were collected at different time points and Diapin in plasma was measured by LC-MS/MS system (n = 5). <b>C.</b> Insulin secretion by INS-1 cells. INS-1 cells were treated with various concentration of Diapin for 1 hour and the supernatants were collected for insulin measurement. *<i>P</i><0.05, compared with that in the absence of Diapin.</p

Effect of Diapin on non-fasting blood glucose levels in <i>KKay</i> diabetic mice.

<p>(A) Male <i>KKay</i> diabetic mice and (<b>B</b>) adult male C57BL/6J mice under non-fasting condition were given either vehicle in control groups or Diapin (1 mg/g bw, n = 9/group) in the treated groups. After Diapin loading, the blood glucose levels were measured every 30 min. *<i>P</i><0.05, compared with the controls.</p

Effect of Diapin on blood glucose levels in diabetic mice.

<p>After oral loading of Diapin (Δ, 0.5 mg/g; ▪, 1 mg/g) by gavage, OGTT was performed in male (<b>A</b>) <i>ob/ob</i> (n = 10), (<b>B</b>) <i>db/db</i> (n = 10) diabetic mice, (<b>C</b>) <i>KKay</i> (n = 9), and (<b>D</b>) the high fat diet-induced obesity mice (n = 10), in which the wild type male C57BL/6J mice were fed with high fat diet for ten weeks. *<i>p</i><0.05, compared with the controls.</p